Month: October 2018

To further challenge the selectivity of these novel compounds, we chose four of these for more detailed characterization. These four molecules fulfill concepts of drug likeness ( Fig. 5A ) ( 26 , 27 ). Orexigenic candidate (oC) compounds A and B doubled food intake, whereas the two anorectic candidate (aC) compounds C and D reduced food intake by more than 50% in zebrafish ( Fig. 5 , B to E). None of the candidate compounds modulated the responsiveness to visual ( Fig. 5F ) or acoustic ( Fig. 5G ) stimuli, spontaneous activity ( Fig. 5H ), habituation ( Fig. 5I ), and lethargy ( Fig. 5J ). aC compound D bound to PBR, 5-HT2B, and 5-HT2C receptor with nanomolar affinity ( Fig. 5 , K and L), whereas the other candidate small molecules did not bind to any of the 43 human neuronal targets with a millimolar affinity ( Fig. 4C ). Norfenfluramine, the active metabolite of the former anti-obesity drug fenfluramine, binds to 5-HT2B and 5-HT2C receptors with similar affinities to aC D ( 28 ). 5-HT2C receptor activity is considered the driver for fenfluramine’s anorectic effect and is the primary target of the recently approved anti-obesity agent lorcaserin ( 4 , 5 ). To detect potential toxic and mutagenic small-molecule effects, we monitored zebrafish development under the exposure of candidate drugs in vivo using light microscopy from the single-fertilized cell stage to the 6 dpf behaving larvae. None of the candidates had a significant impact on embryological mortality, developmental defects, or temporal delays, or on the body length at 5 dpf, whereas EtOH exposure significantly reduced survival after hatching and led to lordosis as reported previously ( Fig. 5 , M and N) ( 29 ). As we were unable to detect an impact of the candidate compounds on normal vertebrate development, we tested for a drug impact on more subtle behavioral characteristics. These behaviors required the analysis of single fish at high temporal and spatial resolution and therefore are not suitable for high-throughput screening. First, we assessed thigmotaxis (or “wall loving”), which is a validated behavioral index for anxiety in animals. Anxiolytic drugs reduce thigmotaxis, whereas anxiogenic compounds enhance it in zebrafish larvae ( 30 ). Candidate compounds A to D did not modulate the thigmotaxic response in daylight compared to vehicle control, nor did they interfere with the characteristic reduction of thigmotaxis observed with the onset of darkness ( Fig. 5O ). Second, we assessed the impact of the candidate compounds on two sensitive visual behaviors: phototaxis and the optomotor response. Larval zebrafish are attracted by light and averse to darkness, and hence, perform positive phototaxis ( 31 ). Larvae treated with candidate compounds A to D executed phototaxis with similar precision to vehicle-treated animals and reduced their place preference during darkness accordingly ( Fig. 5P ). The optomotor response is an orienting behavior evoked by visual motion ( 32 ). A closed-loop setup presented a grating moving perpendicular to the body axes of an individual zebrafish. The stimulus elicits a turning behavior within the direction of the stimulus. We did not detect a significant impact of candidate compound on the correct execution or the turn angle used during the optomotor response ( Fig. 5Q ). Third, we quantified the responsiveness of larvae within a novel aversive behavioral paradigm. Larvae avoided the presence of noxious stimuli (here, mustard oil) but had no preference if presented a non-noxious stimulus (agar). This preference was not visually mediated as it was detectable during daylight and darkness. Larva treated with the candidate compounds avoided the noxious stimuli analogously to vehicle control ( Fig. 5R ). Fourth, larval zebrafish swam spontaneously in an open arena, and their locomotion exhibited a characteristic segmentation into an individual burst of locomotion, also called a swim bout. We traced larval swim locomotion in the presence of the candidate compounds, and subsequently performed detailed kinematic analysis. Neither larval average swim speed, bout length, bout duration, nor interbout duration was altered by the candidate compounds ( Fig. 5S ). Hence, all the candidate compounds selectively modulated feeding behavior in zebrafish larvae, while they showed no detectable impact on development and did not interfere with the execution of an array of behavioral tasks.

Hogan is running for his second term after first being elected in 2014. He is the second Republican Governor of Maryland in nearly 50 years. Previously he served as Secretary of Appointments under Governor Bob Ehrlich (2003-2007) which involved appointing individuals to positions in the Maryland government. He was also a small businessman and in 2011 he founded Change Maryland, a non-partisan grassroots organization that was a frequent critic of tax increases in the state. Hogan’s father, Lawrence Hogan, Sr., was a US Congressman representing Maryland’s 5 th congressional district from 1969 to 1975. Hogan, Sr. was also Prince George’s County Executive from 1978 to 1982.

The Ford Aspire facelift is powered by a 1.2-litre, three-cylinder TiVCT petrol from the Dragon series churning out 96bhp powerplant which can be found on the current gen Freestyle. The Aspire also comes powered with the 123bhp, 1.5-litre, four-cylinder TDCi diesel engine on offer. Transmission duties will be done by a 5-speed manual gearbox. Ford, however, did not bring the diesel-automatic combo to the Indian market at launch. The only automatic petrol combo can be availed in the Titanium trim and is priced at Rs 8.49 lakh, ex-showroom. The petrol AMT is powered by the 1.5-litre TiVCT engine and is mated to a 6-speed AMT unit. All variants get dual-airbags, ABS and EBD as standard.

The weather and longer exposure didn’t suit some contenders. The 10-week test meant we also had to revise our criteria as several of the 15 contenders went grey – while still beading water. But the heart of the test remained the same: water beading, which we checked throughout. We also factored in ease of application, initial finish, plus that last check on how each section looked at the end. Price was the final factor. Yet while the test was tougher, there were still some familiar names at the top.

Arguably that sentiment applies most strongly to BMW, and by extension Alpina. Nowadays there is a bewildering array of niche-busting models in the BMW line up, and even Alpina was forced down the diesel SUV route, but of course it wasn’t always like that. Once upon a time BMW and Alpina solely occupied themselves with the very finest sports saloons and coupes on the planet. By and large Alpina still does, certainly, though the frustration in some parts at BMW’s endless diversification arguably comes from its simple line up being so effective for so long.

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According to one example provided by a leading multi-franchise dealer, if the lender’s finance rate was 5 per cent interest but the dealer could sign up the customer at 12 per cent, the dealer could reap a kickback of about $10,000 on a loan for a $50,000 car. That’s in addition to the dealer’s profit from the sale of the car itself.

The base LT specification also enjoys all the new safety/driver assistance technology of the other Acadia models, with the exception of auto-park and front park assist. That means you get the 360-degree camera that offers up to 17 variations of the screen view (including a trailer hitch guidance view), the lateral impact avoidance system that’ll help prevent you from knocking down a filtering motorcycle when you change lanes on a congested motorway, and the Holden Eye — an imminent collision warning system that’s one of the best in cardom and future-proofs the Acadia for further autonomous driving upgrades. The latter is one of the keys to Acadia being able to identify pedestrians and cyclists, and automatically apply the brakes at urban speeds if required.

The Achilles W101 X is the “surprise” guest of this Auto Bild test. If the magazine did not have high hopes for this Indonesian tyre, it was pleasantly surprised by its winter performances. It costs just over half the price of a Michelin tyre – the 4 tyres cost Auto Bild 350€ versus 675€ for the Latitude Alpin 2 – and yet it manages to hold its own. Although its steering response is sometimes slow and it understeers in the wet, Auto Bild drivers never found themselves in difficulty. However, its price must be put into perspective since it has the highest rolling resistance which in the long term means higher fuel consumption.

The pieces include two unisex suede sneakers inspired by Lagerfeld’s iconic style — a tuxedo jacket, high white collar, tie and sunglasses. In accordance with this theme, the women’s line has a tuxedo-inspired T7 track jacket with matching pants and a T7 jumpsuit, both stylish plays on Puma’s iconic Track Jacket with 7mm stripes. Priced at RM170 to RM670, pieces from the collection are now available for purchase here .